The present invention relates to a pharmaceutical formulation of omeprazole in the form of gastroprotected microgranules having an improved stability over time.
The present invention additionally applies to the process for the manufacture of the said microgranules and to the pharmaceutical preparations containing them.
Omeprazole or 5-methoxy-2-[[(4-methoxy-3,5-di-methyl-2-pyridinyl)methyl]sulphinyl]-1-benzimidazole is known as a powerful inhibitor of acidic gastrointestinal secretion (Swedish Patent No. 78 04231) and can be used in the treatment of gastric and duodenal ulcers.
It is also known that omeprazole readily degrades in acidic medium and in neutral medium. The degradation half-life of omeprazole is ten minutes at a pH of less than 4, eighteen hours at a pH equal to 6.5 and approximately 300 days at a pH equal to 11.
For this reason, pharmaceutical dosage forms of omeprazole for oral administration are gastroprotected so that the active principle reaches the small intestine without being degraded.
During long-term storage under normal conditions of use (temperature of 25xc2x0 C. and degree of humidity of the order of 40-75%), it has been observed that conventional formulations are not stable over time. The degradation of the omeprazole, the appearance of harmful degradation products and colouring of the formulation have been observed.
This is because the stability of omeprazole is also affected by moisture, heat, the presence of organic solvents, even in the form of traces, and, to a lesser extent, light. Organic solvents are generally used in the process for the manufacture of omeprazole formulations, which it is desired to avoid for ecological reasons.
In order to improve the duration of stability on storage of gastroprotected formulations comprising omeprazole or an alkaline salt of omeprazole, the active principle is often combined with an excipient, such as:
an alkaline substance (see Patent Application EP-247,983), for example a sodium, potassium, calcium or aluminium salt of an organic acid, such as phosphoric acid, carbonic acid or citric acid,
an antiacid substance, for example an aluminium, magnesium or calcium oxide or hydroxide,
a pharmaceutically acceptable organic buffer substance, such as a basic amino acid or one of their salts, in particular trihydroxymethylaminomethane,
an inert substance, such as mannitol (see Patent Application of EP-646,006) or titanium dioxide (see Patent Application WO 96/37 195),
an agent which dehydrates, during the final packaging of the formulation.
However, it has been observed that the stability of the formulations of the prior art is unsatisfactory and the aim of the present invention is to provide a gastroprotected formulation of omeprazole microgranules which is stable to coloration, the stability to long-term storage of which is improved and which additionally exhibits the desired therapeutic properties, that is to say a degree of resistance to dissolution in acidic medium and rapid solubility in neutral medium.
The object of the present invention is thus to provide gastroprotected microgranules of omeprazole which exhibit dissolution profiles corresponding to the targeted therapeutic application and which are advantageously stable over time.
The present invention relates to a novel gastro-protected formulation of omeprazole comprising at least one hydrophobic substance chosen in order to increase the stability of the active principle while obtaining the desired dissolution profile. The Applicant Company has in particular optimized the composition of such a formulation by selecting combinations of several hydrophobic substances in order to achieve the objective of the present invention.
The microgranules of omeprazole which are the subject-matter of the present invention are advantageously devoid:
of alkaline compounds in the form of salts,
of ionic surface-active agents, such as the lauryl sulphate commonly used to stabilize omeprazole, and
of traces of organic solvents.
The microgranules of omeprazole according to the invention each comprise an active layer comprising the active principle and an external gastroprotective layer comprising a gastroprotection agent and are characterized in that they comprise at least one hydrophobic substance.
Hydrophobic substances will be chosen which do not react chemically with omeprazole, which can be easily employed during formulation, which are compatible with the excipients used and which make it possible to obtain the dissolution and release profiles desired for the targeted therapeutic application.
In the active layer, the hydrophobic substance preferably represents between 5 and 40% by weight of the omeprazole.
In a preferred embodiment, the active layer comprising the omeprazole is advantageously coated with at least one protective layer.
This protective layer can comprise a diluent substance or a coating agent in combination with a hydrophobic plasticizer.
The gastroprotection agent can be combined, in the external gastroprotective layer, with a hydrophobic agent preferably chosen from glycerides.
According to a particularly advantageous embodiment, the microgranules according to the invention use a combination of different hydrophobic agents which makes it possible to improve the stability of the formulation.
According to a preferred embodiment, the microgranules according to the invention comprise:
a layer of active principle comprising omeprazole, a binder chosen from any pharmaceutically acceptable binder, a hydrophobic substance and a substance which dissolves the active principle,
a first protective layer comprising one or more pharmaceutically acceptable diluent substances and a binder chosen from any pharmaceutically acceptable binder,
a second hydrophobic protective layer comprising a coating agent and a hydrophobic plasticizer,
a gastroprotective layer comprising an enteric film-forming agent, a plasticizer and a hydrophobic substance.
The layer of active principle advantageously comprises a hydrophobic substance of the fatty substance type advantageously chosen from silicone oils: it preferably represents between 5 and 40% of the weight of active principle.
A non-ionic surfactant, preferably chosen from polysorbates (Montanox 80(copyright) or Montane 20-60(copyright)), is also included in this layer in a proportion of 5 to 15% with respect to the weight of active principle.
The active layer advantageously comprises a binder chosen from pharmaceutically acceptable binders, in this case hydroxypropylmethylcellulose, the proportion by mass of which represents 30 to 50% with respect to the weight of active principle.
The first protective layer advantageously comprises an inert substance chosen particularly from pharmaceutically acceptable diluents, including mannitol (which is non-hygroscopic), in a proportion by mass of 100 to 300% and preferably 200% of the weight of the active principle.
This layer also comprises a binder chosen from pharmaceutically acceptable binders, advantageously hydroxypropylmethylcellulose, in a proportion of 10 to 30% and preferably 20% of the weight of mannitol.
It is optionally possible to include, in this protective layer, a lubricant chosen from pharmaceutically acceptable lubricants, in this case talc (which is non-hygroscopic), in a proportion of 0 to 100% of the weight of the active principle.
The second protective layer is composed of a water-soluble coating agent chosen from pharmaceutically acceptable film-forming agents and advantageously hydroxypropylmethylcellulose, in a proportion of 1 to 10%, preferably 5%, of the weight of microgranules obtained after coating on the first protective layer.
Use will advantageously be made, in the second protective layer, of a hydrophobic plasticizer, such as Myvacet(copyright), in a proportion of 10 to 30% of the dry varnish of the coating agent used.
Use will optionally be made of a lubricating agent chosen from pharmaceutically acceptable lubricants, advantageously talc (which is non-hygroscopic), in a proportion of 10 to 50%, preferably 15%, of the dry varnish of the coating agent used.
The external gastroprotective layer comprises a gastroprotective film-forming agent, advantageously a methacrylic acid copolymer, such as Eudragit L30D(copyright), in a proportion of 15 to 30%, preferably 20%, of polymer, on a dry basis, with respect to the mass of microgranules which is treated.
There will advantageously be included, with the gastroprotective film-forming agent, one or more hydrophobic substances chosen from the waxes and oils often used in the pharmaceutical industry, preferably Gxc3xa9lucire 50-13(copyright), in a proportion of 5 to 20% of the dry varnish of the film-forming agent used.
Use can optionally be made, for the external gastroprotective layer, of a plasticizer chosen from pharmaceutically acceptable plasticizers, preferably triethyl citrate, representing from 5 to 20%, advantageously 10%, of the weight of dry varnish of the film-forming agent used.
Use will optionally be made, in order to reinforce the resistance to moisture of the gastroprotective layer, of a lubricating agent chosen from pharmaceutically acceptable lubricants, advantageously talc.
According to a preferred embodiment of the present invention, the active layer is coated on a neutral core composed, for example, of sucrose and starch, the diameter of which is between 700 and 900 microns.
The microgranules according to the invention will preferably have a particle size of between 0.5 and 3 mm, more preferably between 0.7 and 2 mm.
Another subject-matter of the present invention is a process for the preparation of the microgranules according to the invention. This process is characterized in that it is carried out in aqueous medium, without using any organic solvent.
The microgranules described in the present invention will be obtained by using any appliance appropriate for the preparation and the coating of microgranules which is well known to a person skilled in the art and, in particular, appliances of conventional turbomixer, perforated turbomixer or fluidized air bed type.
According to a preferred embodiment, the microgranules according to the invention are obtained by coating on a neutral core, preferably in a fluidized air bed, by successively spraying:
an aqueous suspension of omeprazole and a hydrophobic substance,
optionally an aqueous suspension of a diluent substance, and/or
an aqueous suspension of a coating agent and a hydrophobic plasticizer, and
an aqueous suspension of the gastroprotection agent, also known as enteric film-forming agent.
According to a very particularly valued embodiment, the microgranules according to the invention are coated on a neutral core, in a fluidized air bed, by successively spraying:
an aqueous suspension of omeprazole and a silicone oil,
an aqueous suspension of mannitol,
an aqueous suspension of hydroxypropylcellulose, and
an aqueous suspension of the gastroprotection agent.
Each spraying stage is advantageously followed by sieving and drying at a temperature below the melting temperature of each of the compounds forming part of the composition of the microgranules at the said stage.
The microgranules obtained according to this process advantageously comprise less than 1.5%, preferably 0.5%, by weight of water.
Finally, a subject-matter of the present invention is the pharmaceutical preparations comprising the microgranules according to the invention which are capable of being obtained by the process described above; these preparations will advantageously be in the form of gelatin capsules comprising 5 to 60 mg approximately of omeprazole.